The proposed experiments will determine the anatomical and functional connections among specific neurons in the brainstem and spinal cord that are involved in the modulation of nociception. The neuronal cell groups to be examined include substance P and met-enkephalin neurons in the ventromedial medulla (VMM) and the periaqueductal gray (PAG), the A7 catecholamine cell group, a group of enkephalin neurons in the dorsolateral pontine tegmentum (DLPT) that innervate the spinal cord dorsal horn, and GABA neurons in the DLPT. Anatomical connections among these identified neurons will be determined using immunocytochemical methods to characterize their neurotransmitters, projections, and the location of synapses formed by these neurons. Functional connections among these immunochemically-identified neurons will be established using pharmacological and electrophysiological approaches. Pharmacological studies will determine changes in nociception induced by electrical or chemical activation of selected, identified neurons and the effect of subsequent microinjection of receptor agonists or antagonists in the regions to which these neurons project. Electrophysiological studies will characterize the response properties of spinally-projecting enkephalin and noradrenergic A7 neurons, and determine the functional connections of substance P and enkephalin neurons in the VMM and the PAG, and GABA neurons in the DLPT, that project to these descending neurons. The importance of the proposed experiments is related to the contributions they will make toward understanding the mechanisms of endogenous pain modulation in the brainstem that also control nociceptive responses in the spinal cord. The ultimate goal of this research is to understand the pain modulatory circuits in sufficient detail to allow the derivation of a computational model of these neuronal circuits that could be used to develop more effective pain control methods. It is hoped that safer and more effective pain controls methods could be developed that do not depend on opioid drugs with their attendant serious side effects and addiction liability.